PMID- 24510228
OWN - NLM
STAT- MEDLINE
DCOM- 20141216
LR  - 20211021
IS  - 1432-0428 (Electronic)
IS  - 0012-186X (Linking)
VI  - 57
IP  - 5
DP  - 2014 May
TI  - A PGC-1alpha- and muscle fibre type-related decrease in markers of mitochondrial 
      oxidative metabolism in skeletal muscle of humans with inherited insulin 
      resistance.
PG  - 1006-15
LID - 10.1007/s00125-014-3187-y [doi]
AB  - AIMS/HYPOTHESIS: Insulin resistance in obesity and type 2 diabetes is related to 
      abnormalities in mitochondrial oxidative phosphorylation (OxPhos) in skeletal 
      muscle. We tested the hypothesis that mitochondrial oxidative metabolism is 
      impaired in muscle of patients with inherited insulin resistance and defective 
      insulin signalling. METHODS: Skeletal muscle biopsies obtained from carriers 
      (n = 6) of a mutation in the tyrosine kinase domain of the insulin receptor gene 
      (INSR) and matched healthy controls (n = 15) were used for discovery-mode 
      microarray-based transcriptional profiling combined with biological pathway 
      analysis. Findings were validated by quantitative real-time PCR, immunoblotting 
      and activity assays. RESULTS: In INSR mutation carriers, insulin resistance was 
      associated with a coordinated downregulation of OxPhos genes in skeletal muscle. 
      This was related to a 46% decrease in mRNA levels (p = 0.036) of peroxisome 
      proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), and 25-50% lower 
      protein content of OxPhos subunits encoded by mitochondrial (ND6, p = 0.042) and 
      nuclear DNA (UQCRC1, p = 0.001; SDHA, p = 0.067; COX5A, p = 0.017 and ATP5B, 
      p = 0.005), as well as reduced citrate synthase activity (p = 0.025). Moreover, 
      mutation carriers showed a marked reduction in type 1 muscle fibres (35% vs 62%, 
      p = 0.0005) and increased type 2a fibres (53% vs 32%; p = 0.002) compared with 
      controls. There were no differences in protein content and phosphorylation of 5' 
      AMP-activated protein kinase, p38 mitogen-activated protein kinase, Erk1 and 
      Erk2. CONCLUSIONS/INTERPRETATION: These data indicate that inherited insulin 
      resistance coincides with reduced mitochondrial oxidative capacity in a PGC-1alpha- 
      and muscle fibre type-related manner. Whether this co-existence is directly or 
      indirectly related to insulin resistance remains to be elucidated.
FAU - Kristensen, Jonas M
AU  - Kristensen JM
AD  - Department of Endocrinology, Odense University Hospital, Klovervaenget 6, 4, 5000, 
      Odense C, Denmark.
FAU - Skov, Vibe
AU  - Skov V
FAU - Petersson, Stine J
AU  - Petersson SJ
FAU - Ortenblad, Niels
AU  - Ortenblad N
FAU - Wojtaszewski, Jorgen F P
AU  - Wojtaszewski JF
FAU - Beck-Nielsen, Henning
AU  - Beck-Nielsen H
FAU - Hojlund, Kurt
AU  - Hojlund K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140209
PL  - Germany
TA  - Diabetologia
JT  - Diabetologia
JID - 0006777
RN  - 0 (Antigens, CD)
RN  - 0 (PPARGC1A protein, human)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.10.1 (INSR protein, human)
RN  - EC 2.7.10.1 (Receptor, Insulin)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Adult
MH  - Antigens, CD/genetics
MH  - Case-Control Studies
MH  - Family Health
MH  - Female
MH  - Heterozygote
MH  - Humans
MH  - Insulin Resistance/*genetics
MH  - Male
MH  - Middle Aged
MH  - Mitochondria/*metabolism
MH  - Muscle, Skeletal/*metabolism
MH  - Mutation
MH  - Oligonucleotide Array Sequence Analysis
MH  - Oxidative Phosphorylation
MH  - Oxygen/*metabolism
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
MH  - Phosphorylation
MH  - Protein Structure, Tertiary
MH  - Receptor, Insulin/genetics
MH  - Signal Transduction
MH  - Transcription Factors/*metabolism
MH  - Transcription, Genetic
MH  - Young Adult
EDAT- 2014/02/11 06:00
MHDA- 2014/12/17 06:00
CRDT- 2014/02/11 06:00
PHST- 2013/10/15 00:00 [received]
PHST- 2014/01/17 00:00 [accepted]
PHST- 2014/02/11 06:00 [entrez]
PHST- 2014/02/11 06:00 [pubmed]
PHST- 2014/12/17 06:00 [medline]
AID - 10.1007/s00125-014-3187-y [doi]
PST - ppublish
SO  - Diabetologia. 2014 May;57(5):1006-15. doi: 10.1007/s00125-014-3187-y. Epub 2014 
      Feb 9.